Browsing by Author "Soler Polo, Diego"
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Item Proton Transfer in Guanine-Cytosine Base Pairs in B-DNA(Journal of Chemical Theory and Computation, 2019) Soler Polo, Diego; Mendieta Moreno, Jesús I.; G. Trabada, Daniel; Mendieta, Jesús; Ortega, JoséA double proton transfer reaction in a guanine-cytosine (GC) base pair has been proposed as a possible mechanism for rare tautomer (G*C*) formation and thus a source of spontaneous mutations. We analyze this system with free energy calculations based on extensive Quantum Mechanics/Molecular Mechanics simulations to properly consider the influence of the DNA biomolecular environment. We find that, although the G*C* rare tautomer is metastable in the gas phase, it is completely unstable in the conditions found in cells. Thus, our calculations show that a double proton reaction cannot be the source of spontaneous point mutations. We have also analyzed the intrabase H transfer reactions in guanine. Our results show that the DNA environment gives rise to a large free energy difference between the rare and canonical tautomers. These results show the key role of the DNA biological environment for the stability of the genetic code.Item Two-step ATP-driven opening of cohesin head.(Scientific Reports, 2017) Marcos Alcalde, Íñigo; Mendieta Moreno, Jesús I.; Puisac, Beatriz; Gil Rodríguez, María Concepción; Hernández Marcos, María; Soler Polo, Diego; Ramos, Feliciano J.; Ortega, José; Pié, Juan; Mendieta, Jesús; Gómez Puertas, PaulinoThe cohesin ring is a protein complex composed of four core subunits: Smc1A, Smc3, Rad21 and Stag1/2. It is involved in chromosome segregation, DNA repair, chromatin organization and transcription regulation. Opening of the ring occurs at the “head” structure, formed of the ATPase domains of Smc1A and Smc3 and Rad21. We investigate the mechanisms of the cohesin ring opening using techniques of free molecular dynamics (MD), steered MD and quantum mechanics/molecular mechanics MD (QM/MM MD). The study allows the thorough analysis of the opening events at the atomic scale: i) ATP hydrolysis at the Smc1A site, evaluating the role of the carboxy-terminal domain of Rad21 in the process; ii) the activation of the Smc3 site potentially mediated by the movement of specific amino acids; and iii) opening of the head domains after the two ATP hydrolysis events. Our study suggests that the cohesin ring opening is triggered by a sequential activation of the ATP sites in which ATP hydrolysis at the Smc1A site induces ATPase activity at the Smc3 site. Our analysis also provides an explanation for the effect of pathogenic variants related to cohesinopathies and cancer.